PXD017317

PXD017317 is an original dataset announced via ProteomeXchange.

Title	Polypharmacological perturbation of the 14-3-3 adaptor protein interactome stimulates neurite outgrowth
Description	Targeting protein-protein interactions (PPIs) is a promising, but under-exploited, approach in the development of drugs for many indications. 14-3-3 proteins are a family of adaptor molecules with ubiquitous and critical functions in dozens of cell signaling networks. 14-3-3s bind to hundreds of ‘client proteins’ in a stereotyped fashion, altering client protein function, localization and stability. 14-3-3s are especially abundant in the central nervous system, and the small molecule fusicoccin-A (FC-A), a tool compound that can be used to manipulate 14-3-3 PPIs, enhances neurite outgrowth in cultured neurons. New semisynthetic FC-A derivatives with improved binding affinity for 14-3-3 complexes have recently been developed. Here we employ a series of screens that identify these compounds as potent inducers of neurite outgrowth through a polypharmacological mechanism. Using proteomics and x-ray crystallography, we discover that these compounds extensively perturb the 14-3-3 interactome through a unique and previously undescribed mechanism involving direct stabilization and inhibition of 14-3-3 PPIs. These results provide new insights into the development of drugs to target 14-3-3 PPIs, a potential therapeutic strategy for CNS diseases.
HostingRepository	PRIDE
AnnounceDate	2020-03-31
AnnouncementXML	Submission_2020-03-30_23:45:22.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD017317
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Sara Luiza Banerjee
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	Phospho; Deamidated; phosphorylated residue; Oxidation; monohydroxylated residue; Carbamidomethyl; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2020-01-29 04:03:40	ID requested
⏵ 1	2020-03-30 23:45:23	announced

Kaplan A, Andrei SA, van Regteren Altena A, Simas T, Banerjee SL, Kato N, Bisson N, Higuchi Y, Ottmann C, Fournier AE, Polypharmacological Perturbation of the 14-3-3 Adaptor Protein Interactome Stimulates Neurite Outgrowth. Cell Chem Biol, 27(6):657-667.e6(2020) [pubmed]

submitter keyword: Polypharmacology, axon, 14-3-3, regeneration, Rap1

Nicolas Bisson
contact affiliation	Centre de recherche du Centre Hospitalier Universitaire (CHU) de Quebec-Université Laval, Québec, QC, Canada Centre de recherche sur le cancer de l’Université Laval, Québec, QC, Canada PROTEO-Quebec Network for Research on Protein Function, Engineering, and Applications, Québec, QC, Canada Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, QC, Canada
contact email	Nick.Bisson@crchudequebec.ulaval.ca
lab head
Sara Luiza Banerjee
contact affiliation	Centre de recherche sur le cancer – Université Laval
contact email	banerjee.sara@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017317
     1. Label: PRIDE project
     2. Name: Polypharmacological perturbation of the 14-3-3 adaptor protein interactome stimulates neurite outgrowth